David Jackman, MD
Dana-Farber Cancer Institute partnered with CancerConnect so that patients could ask David Jackman, MD, their questions about lung (thoracic) cancer. Dr. Jackman is a thoracic oncologist in the Lowe Center for Thoracic Oncology at Dana-Farber and assistant professor of medicine at Harvard Medical School. You can find patients' questions and Dr. Jackman's answers below.
Treatment for Stage III Lung Cancer
Q: My sister has Stage III lung cancer and presented with anemia, nausea and weight loss. They didn't want to treat her until they figured out what was going on with the nausea, so we waited for 2 months while they did tests. Now they are finally moving, but still don't know why she is anemic and can barely eat. We meet with the radiation oncologist Friday and want to know what to ask. Is there a specific kind of treatment modality we should be asking about? Tomotherapy, CyberKnife, proton therapy? I just don't know enough about it. We are near enough to Chicago that we have everything available, just want to make sure our physician offers the best option.
A: When we think about Stage III lung cancer generally, we think about providing both local therapy (radiation and/or surgery) as well as systemic therapy (chemotherapy). There is not one standard approach, and the specifics of the choice and timing of the local therapies may vary from center to center. With respect to radiotherapy in Stage III lung cancer, we often consider delivering radiation together with chemotherapy in those patients who are well enough to handle this combination. The radiation should be delivered conformally — that is, the radiation field is shaped to encompass the areas of tumor involvement to optimize the delivery of radiation to the tumor and limit the dose of radiation to surrounding normal tissues.
We generally do not use cyberknife or proton therapy in radiation for Stage III lung cancer. "CyberKnife" is a form of what we call stereotactic radiation, delivering a very focused beam of radiation to a small, well defined area. In lung cancer, this is primarily used in small, local tumors that haven't spread and would otherwise have been surgically removed but the patient cannot tolerate a surgical operation for some reason. It is not feasible for larger fields in which we need to irradiate both a tumor and mediastinal lymph nodes, as in most cases of Stage III lung cancer. Furthermore, the safety of stereotactic radiation for tumors located toward the center of the chest is a major concern due to the potential deleterious effect on some of the main airways in that area.
Proton therapy is an exciting advance in radiation therapy, but its use in lung cancer remains investigational. There are technical challenges surrounding the delivery of protons to lung tumors, so that this type of radiation has not been adopted as the standard practice at this time.
Goal of Stage IV Lung Cancer Treatment
Q: My father has been diagnosed with metastatic cancer which has spread to his spine. Primary is unknown till now as I received FNAC (fine needle aspiration cytology) report just yesterday. I am waiting for biopsy results. I have read that Stage IV cancer is incurable in majority of cases. So should we go for treatment that can reduce his pain, or we can expect some kind of cure?
A: For lung cancers that have spread to a distant area outside the lungs — such as the bone — there are indeed treatment options available. Our currently available treatment options don't have a good track record of being able to cure Stage IV lung cancer, although they certainly have the potential to prolong survival and improve symptoms and quality of life. It is impossible to predict whether treatment is going to be beneficial in a specific patient. However, in earlier clinical trials of patients who were fit enough to tolerate chemotherapy for Stage IV disease, half of patients received chemo and half received supportive care alone. In such trials, the group that received chemo had a longer median overall survival, as well as improved scores on quality of life measures.
Whether or not your father opts to pursue chemotherapy, we should still be committed to trying to do whatever else we can to improve his quality of life. This might at some point include consideration of radiation to any areas of painful or compromising metastases to the spine or elsewhere. It might also include referral to a palliative care specialist. In a trial of patients with metastatic non-small cell lung cancer, patients who received early referral to a palliative care team experienced significant improvements in both quality of life and mood compared to those who did not receive such early referral. Such palliative care was not necessarily in place of chemotherapy treatment, and in many cases was in addition to treatment.
Treatment for KRAS-positive Stage IV NSCLC (non-small cell lung cancer)
Q: I have NSCLC Stage IV adenocarcinoma with KRAS-positive non-wild 12D. Is there anything in the works that could help me? The Alimta and carboplatin had to be stopped because of a most severe edema. My liver transplant was done by Dr. Cosimi 18 years ago and has been fantastic.
A: KRAS mutations are one of the most common types of mutations in non-small cell lung cancer. To date, these mutations have also been quite hard to target effectively. It is difficult to directly target the KRAS protein itself. Instead, investigators have tried to target proteins that act downstream of KRAS. While there are no medications that have specifically been approved to target KRAS¬-mutated lung cancer, there are many clinical trials that are currently enrolling. One strategy, combining the approved chemotherapy docetaxel with an investigational inhibitor of a protein called MEK did show early promise in a Phase II study last year.
There is now a randomized Phase III trial that is open at several centers across the country, including Dana-Farber Cancer Institute, where I work, in which patients with ¬KRAS-mutated, Stage IV non-small cell lung cancer are randomly assigned to receive either docetaxel alone or docetaxel plus the addition of a MEK inhibitor. We hope that this and other trials will help us to find ways of effectively targeting KRAS in lung cancer.
Fatigue and Nutrition Challenges in Stage IV Lung Cancer
Q: My brother has just had his 5th round of chemo. His 6th and last is next week. His PET scan a few weeks ago showed a 50% reduction in his cancer (he was diagnosed with Stage IV in 11/10.). Is there anything we should be doing/asking at this point? Right now he's lost 50+ pounds and is very weak. Walking across the room is exhausting for him. I still fear that he's not getting the nutrition that he needs. Or is this normal for this stage in chemo? They're doing some kind of double dose; he goes for chemo and back next week for a 1/2 hour session. He has been drinking plenty of fluids (anything as cold as possible) and a couple of cups of soup/day, plus maybe some yogurt or piece of fruit. I'm glad he's able to keep it down now, but it just doesn't seem like much. Is this the time in his treatments when his platelets are at their lowest and this is why he's so weak? He tells me that he's so tired of feeling tired/weak all the time.
A: Fatigue at this point in your brother's treatment course is one of the most common and challenging problems we face. Often fatigue is not just related to one specific thing but can be related to many contributing factors: we can be fatigued due to the effects of the cancer, the effects of chemotherapy, the effects of other medications like pain killers, the effects of anemia (low red blood cells), decreased nutritional and fluid intake, depression, or any number of other things.
While it is hard to make a specific recommendation on your brother's case from afar, it is certainly worth asking his doctor about possible medication effects or drug interactions, asking whether his hematocrit (red blood cell level) warrants considering a blood transfusion, and asking to see a nutritionist with expertise in advising cancer patients. His level of fatigue may also be a factor in whether or not to proceed with additional chemotherapy at this time or to give him a break in therapy for now.
Low-Dose Brain Radiation to Prevent Brain Mets (Metastases)
Q: Does low-dose brain radiation help to prevent brain mets for Stage IV non-small cell lung cancer?
A: It has been shown that preventive brain radiation, otherwise known as prophylactic cranial irradiation (PCI), has been shown to reduce the risk of brain metastases and improve survival in small cell lung cancer. However, the same has not been shown in non-small cell lung cancer. Investigators are looking to see if there might be a specific group of patients within non-small cell lung cancer who might specifically benefit from such an intervention, but this has not been determined. For now, brain radiation in non-small cell lung cancer has been reserved to those patients with known spread of cancer to their brain.
Scar Tissue after Surgery for Stage III NSCLC
Q: I was diagnosed with Stage III non-small cell carcinoma in 2008 and had a lobectomy (upper left lobe), chemo, radiation, surgery and treatments to correct the problem. It's not until very recently that I have had severe pain on my left side from my pectoral muscle to where the scar is from the lobectomy under my left armpit. I was recently admitted to the hospital where the surgery had been performed after two days of coughing blood, which was diagnosed as internal blood vessels and scar tissue creating the situation. I was also on 5mg/day of Coumadin to prevent clotting which I have had a history of PE's (pulmonary emboli). They inserted a catheter through my groin (angiogram), located the source and stopped the bleeding. They also inserted a filter in my main stomach vein to prevent clots from entering from my legs and entering my heart and lungs. Is this problem typical after treatment?
A: It would be a reach to call your situation typical, though it is certainly in the realm of possibility. Aggressive therapy for Stage III lung cancer does carry potential short-term and long-term risks. On the other hand, I am thrilled to hear that you are otherwise alive and well some 5 years after your cancer diagnosis. Keep up the fight.
Screening for Lung Cancer
Q: Is screening for lung cancer recommended?
A: Cancer screening is a challenging issue. Ultimately, a screening test cannot merely detect more cancers than before. That detection has to result in an improvement in mortality to make the screening worthwhile, and it has to do so in a way that is safe and that doesn't lead to many missed cases (false negatives). To date, the only cancer screening tests that have met these criteria are mammograms for breast cancer, Pap smears for cervical cancer, and sigmoidoscopy and fecal occult blood testing for colon cancer. Colonoscopy is assumed to meet these criteria, though it has not yet formally been shown to do so in a large randomized trial.
With respect to lung cancer, screening with chest x-rays was studied a few decades ago but was not shown to improve lung cancer-related mortality. More recently, low dose computed tomography (CT) scans have been studied as a possible screening tool. In a large randomized trial of asymptomatic patients with significant smoking histories (had smoked the equivalent of at least a pack of cigarettes per day for 30 years) and who were between the ages of 55-74, subjects were randomized to receive either an annual chest X-ray or an annual low-dose CT scan for three years. The group who underwent CT scans were found to have a lower risk of death from lung cancer (the relative reduction in the rate of death from lung cancer was 20%), as well as a 6.7% improvement in death from any cause. These data are certainly encouraging, although there are many more aspects to lung cancer screening that aren't captured in those numbers: Who should be screened? Will there be long term risks from radiation exposure? And will we be able to afford this kind of screening across an entire population?
At present, many organizations have endorsed the use of low-dose CT screening for lung cancer in a specific population, namely high-risk patients like the one studied in the National Lung Screening Trial: patients ages 55-74 who had previously smoked at least 30 pack-years (multiply the number of packs per day x the number of years smoked) and are either still smoking or have quit within the last 15 years. Some of these organizations include the National Comprehensive Cancer Network, the American Society of Clinical Oncology, the American College of Chest Physicians, and the American Cancer Society. However, the United States Preventive Health Services Task Force, which is perhaps the biggest policy-influencing committee on this topic, has not yet adopted lung cancer screening by CT scan as a recommended guideline at this time.
Investigative Drugs for Stage IV NSCLC
Q: Are there any new drugs that are going to be available soon for Stage IV nsclc? I have had carboplatinum and paclitaxel.
A: There are many exciting avenues of research for non-small cell lung cancer at this time. Some of the most recently approved drugs in lung cancer have been oral medications that target specific proteins that are the result of gene mutations or rearrangements in your cancer's cells: erlotinib targets EGFR (epidermal growth factor receptor), while crizotinib targets ALK (anaplastic lymphoma kinase). Each of these genes may be altered in some lung cancers, and these drugs provide a way of attacking those altered proteins.
At present, there are newer agents in clinical trials that are attempting to attack these and other altered proteins in lung cancer. At the American Society of Clinical Oncology annual meeting earlier this month in Chicago, we saw evidence of some activity with drugs targeting EGFR and ALK, as well as other mutated proteins like BRAF and ROS. Whether it is still too premature to predict whether there will be sufficient activity and safety to warrant the ultimate approval of these drugs, there is at least hope of success for a strategy of studying an individual's cancer for specific driving mutations and then trying to target that protein or pathway.
Another area that is generating excitement is the use of immunotherapy in lung cancer. Specifically, there are a number of agents that are being developed to attempt to spur the immune system into attacking one's cancer. Antibodies that inhibit programmed death 1 (PD-1) found on the surface of activated T-cells try to allow the immune system to recognize cancer cells as foreign and then attack them; antibodies that inhibit programmed death 1 ligand-1 (PD-L1) on tumor cells are trying to do the same thing. These studies are still very early in their development. While there is excitement about these drugs, it will be years before we can determine whether there is sufficient efficacy and safety to warrant their approval.
NED (no evidence of disease), Remission, Cure
Q: Is there at any time a doctor will say, you're clear of cancer, and how long will it take for him to say it? I was diagnosed with lung cancer in October 2009 and finished chemo and radiation treatment in May 2010. Since then I've had three CT scans; the doctor is pleased with my progress but has never said that I am cured.
A: We wish that we had a perfect test — a special blood test or scan — that could tell us whether your cancer is gone or not. Unfortunately, such a test does not exist, and neither blood tests nor scans can tell us whether there are any remaining cancer cells that elude current detection and may ultimately go on to multiply. What we are left with is time: that is, the longer you go without evidence of cancer on scans, the less likely that the cancer is still around. For lung cancers, the majority of tumors that eventually recur do so within two years. If you get to 2 years without any evidence of cancer recurrence, then your odds are indeed getting better. If you get to 5 years without any evidence of the cancer recurring, at that point the likelihood of your prior cancer recurring is very, very low. While this 5-year timepoint doesn't hold true for all cancers (for example, breast cancer can recur many years later), we start to run the cure flag up the pole if you haven't recurred after 5 years. It doesn't mean that you aren't at risk for new cancers forming, but the chance of the old cancer coming back after 5 years is pretty slim.
Q: My sister passed away from lung cancer in February 2013. I believe it was non-small cell adenocarcinoma. She was diagnosed in July 2012 and was at Stage IV upon diagnosis, with metastases to the brain and liver. Can you estimate how long this was in her body, growing, before it was found? We were told it is a very aggressive type of cancer. The only symptom she had was a backache. I just wonder how long it took to spread. Thank you.
A: Unfortunately, at the time of initial lung cancer diagnosis, 55% of patients will already have metastatic disease, so your sister's course is not an unfamiliar one. We don't have a good way of knowing how long the cancer was in your sister's body. Cancer growth and spread are different in each patient, and even in a particular patient, the growth isn't necessarily linear. That is, just because a tumor grew 25% over a 6-month period, we can't predict that it will necessarily grow 25% over the next 6 months.
Q: I am wondering about bone scans — are they reliable? Why would a bone scan come out 'clean' when in fact it was not? I have heard that a scan shows 'repair,' and if no repair is going on it may come out 'clean' even if it is not.
A: Bone scans, like all scans, have their limitations. With any scan used in cancer, a mass has to be quite sizeable (usually almost a centimeter) and metabolically active to be detectable on something like a bone scan or PET scan. Smaller lesions or lesions that aren't currently very active may not light up one these scans, though it doesn't mean that they aren't malignant. There are other challenges with scans: areas that light up aren't necessarily tumors. In PET/CT's, avid areas may represent cancer, but they may also represent infection or inflammation. In bone scans, areas that light up may represent bone metastases, but they might also represent infection or inflammation from things like arthritis or other degenerative joint diseases.
Debulking for Stage IV Lung Cancer
Q: I have several small tumors in my right lung, on my regional lymph nodes, and perhaps even a small one in the liver that has been detected, but has not grown. I had a small brain tumor a few years ago, and had CyberKnife. I was diagnosed at Stage IV over five years ago at the age of 39, and have thankfully done very well. I have done carbo/Taxol/Avastin, Tarceva/Avastin for almost three years, and crizotinib for 15 months. I know that my cancer has spread, and conventional medical wisdom is that it is only treated with drug therapies, but since I am in good health, strong, and have a small tumor volume overall, why aren't there more options to "clean me out?" Why can't we surgically grab a couple, and do some more CyberKnife, radio-frequency ablation, or radiation to reduce the volume? It seems that less cancer is good cancer, particularly if you rid the body of the cells that were set to spread next! The answer from doctors is always that there is nothing to suggest that it works. Why aren't we doing research in this area, and what would it hurt? Some of these newer procedures seem to be so easy on the body! And since lung cancer is so deadly, doesn't every little bit help?
A: You raise important questions about the value of local therapies to debulk cancer, that is, to try to reduce the overall volume of cancer. When cancers have metastasized to distant sites, they have done so by getting into the bloodstream and setting up shop elsewhere. When we think about the use of surgery and radiation in lung cancer, we generally think about them in two settings: can we encompass all of the cancer with a local therapy in the hopes of a cure, or can we use local therapies to help deal with a focal, specific problem.
The notion of aggressive local therapies in patients with what we call "oligometastatic" disease — cancer in which there is only one site of distant metastasis — has been useful in some cases. In these cases, there is a small chance that for some reason the cancer was able to take hold in only a single spot; so the notion of local therapies to both the primary lung tumor and the solitary site of metastasis has a chance of improving survival.
In patients with more widespread involvement to more than one organ site, the cancer has demonstrated that it has gotten into the bloodstream and has been able to set up shop in multiple areas. In such a case, even if we could safely treat all the sites of visible disease on scans, it is extremely likely that the cancer exists elsewhere at a level too small to be detected and will become evident. In such a setting, the notion of widespread use of aggressive local therapies to target all of the visible disease subjects a patient to all of the potential toxicities of those interventions and hasn't helped us improve cure rates.
However, there may still be a place for selected use of directed local therapies, particularly in patients with ALK-rearranged non-small cell lung cancer (I assume that yours is, on the basis of your successful treatment with crizotinib). Ross Camidge from the University of Colorado recently presented data at the American Society of Clinical Oncology annual meeting earlier this month wherein patients who experienced progression in a single site of disease, while other lesions remained stable, went on to receive focused radiation to the progressing site. This can enable physicians to target the sole site of progression while allowing patients to continue on their targeted chemotherapy, which was otherwise controlling the other areas of disease.
Beyond the scope of your question, I'd like to add that there are clinical trials investigating new targeted agents aimed at ALK-rearranged non-small cell lung cancer, with early data suggesting significant activity, even in patients who have progressed on crizotinib. If your tumor should ultimately progress on crizotinib in a way that warrants consideration of a new line of treatment, you may want to explore one of these trials.
Treatment for Limited Stage Small-Cell Lung Cancer
Q: What are the newest treatments for limited stage small cell lung cancer?
A: The standard treatment of limited stage small cell lung cancer remains fairly similar to years past, namely chest radiation given concurrently with chemotherapy (usually cisplatin plus etoposide). Important questions remain. Investigators are currently exploring the best dose and schedule to deliver radiation. On the chemotherapy end, our search continues for more effective therapies, though there is nothing quite ready for consideration of approval at this time.
Q: My sister (a 51 year-old woman) has a mass in her lung — squamous cell carcinoma NSCLC — and is presenting with anemia (Hemoglobin 7.4) and fevers, also her small intestine appears abnormal in a CT; the lining is thickened. Her PET scan does not light up the small intestine, only the lung. Her upper and lower GI tests were unremarkable. She has not been staged and they don't want to treat the lung CA without first finding out what is going on with the fevers and the small intestine. She continues to lose weight (5'8" and 120 pounds). She has had the fevers since January, about 5 months now, and we are concerned that if they do not start treating the lung cancer, we may lose the window of opportunity to cure her. Should we get a second opinion? What can be causing the fevers and weight loss? Should we insist that they move on to staging? I keep watching my sister get worse. It has taken us 6 weeks to get this information. Can she have lung surgery with the information we have, and move on to answer other questions later?
A: It certainly sounds as if your sister is going through a lot right now and that her case has been challenging. While it is hard to make specific recommendations from afar, I will add the following. First, it is never a bad idea to get a second opinion, particularly in challenging cases. We as doctors should never be too proud or thin-skinned to welcome another opinion on a case. Second, with respect to staging, there are a few general issues. Lung cancer staging typically includes a chest CT with contrast, a PET/CT, and brain imaging (either a brain MRI with gadolinium or a head CT with IV contrast). In patients with what sounds like early stage disease, we typically also want to perform a procedure to look for cancer involvement in the lymph nodes in the mediastinum, the area in the center of the chest between the two lungs. This can be done via a cervical mediastinoscopy (a surgeon makes a cut just above the breast bone (sternum) and uses a scope to explore the area behind the breast bone and biopsy the lymph nodes) or through bronchoscopy with endobronchial ultrasound (a pulmonologist or surgeon inserts a scope through the mouth into the airways and uses an ultrasound at the end of the scope to help guide biopsies of lymph nodes in the surrounding areas). If there is no evidence of involvement of cancer in the mediastinal lymph nodes or in areas outside of the lungs, we then consider cutting out the lung tumor. Alternatively, in patients who are considered too ill to proceed with surgery, we can consider radiation to the tumor.
As for the fevers, this certainly merits workup. We want to make sure that there isn't an ongoing infection to account for fevers, though an infection causing fevers over a 5-month period would be less likely. Cancer itself can cause recurring fevers. There are several other possible causes for recurrent fevers, some of which might not be related to the cancer at all. In any case, it is important at the very least to rule out infection and to accurately stage the tumor as described above. This can help providers to decide whether the tumor is amenable to definitive local therapy, whether by surgery or radiation.
Small-Cell Lung Cancer
Q: I have two related questions regarding small cell lung cancer, specifically neuro-endocrine carcinoma in lungs. A close relative is currently in Phase I trial and while tumors aren't shrinking much, they are stable. She has been approved to continue past the 8-cycle protocol. She was admitted to trial after treatment with cisplatin and etoposide was not effective. My questions are: 1. What is outlook for treatment/chemotherapy for this type of cancer? 2. Is there another medical center doing trials for this type of cancer?
A: Small cell lung cancer is one type of neuroendocrine carcinoma; other types include typical carcinoid, atypical carcinoid, and large cell carcinoma with neuroendocrine features. While initial treatment for these kinds of tumors is fairly similar, treatment strategies may diverge in the second-line setting and beyond, particularly within the realm of clinical trials.
At present, we continue to search for more effective treatment options in small cell lung cancer. First-line therapy with platinum and etoposide can result in responses in many, but not all, patients. When cancer starts growing again, there are a limited number of options to try to control the disease at that point. While there is nothing that is close to approval in small cell lung cancer at this time, there are some interesting early results in some early clinical trials in small cell lung cancer, including trials exploring the use of temozolomide; antibodies against CD56, a protein found on the surface of most small cell lung cancers; and bcl2 inhibitors.
Regarding your second question, many centers are conducting clinical trials for small cell lung cancer. All cancer clinical trials must be registered with the National Cancer Institute, which keeps an active, searchable database of available studies. This database can be explored through the NCI's website at www.cancer.gov. One can search the type and stage of cancer, as well as specify one's zip code and distance willing to travel; the search engine will then reveal a list of potential trials available within the defined radius. Not every patient will be eligible for every trial. Each trial has specific criteria, such as the specific cancer type and the extent of prior therapy. Nonetheless, the search engine will allow your family to explore possible trial options in your area.
Side Effects of Tarceva
Q: I have advanced non-small cell lung adenocarcinoma with the EGFR genetic abnormality. I have seen both you and Dr. Jänne. I have been having chemo with Taxotere along with 100 mg. of Tarceva a day. Several months ago I developed a body rash and a severe eye inflammation which required several visits to an eye doctor to clear up. My oncologist felt that the treatments were causing the problem, so he stopped treatments for about eight weeks. Before beginning treatments I had a CAT scan and a bone scan. The results showed that the cancer had spread in the left lung. It had also spread to my left hip and my left breast. I underwent radiation. The doctor then put me back on the same regimen and again my eyes were affected. The doctor felt it was probably the Tarceva that was causing the problem; he lowered the dose to 50 mg and later to 25mg, but my eye problems continued. I was told to stop the Tarceva again for two weeks. My question is, what do you think I should do? Is Tarceva the only drug being used for my cancer, and do you think Taxotere is helpful with this type of cancer? How do I keep the cancer from spreading further? I am not scheduled for another scan until August, so I do not know the present state of the cancer.
A: Thank you for posting. While this forum is not the ideal way to make specific treatment recommendations, I can offer some more general comments. First, when we're treating in a setting like yours, we're trying to control disease over the long haul. As such, a treatment not only has to be effective; it has to also be tolerable. If we run into reproducible and significant problems even at significantly lowered doses of erlotinib (Tarceva), we may need to make other plans.
Whether or not to continue on docetaxel alone without erlotinib will depend on whether your next set of scans shows continued stability or disease progression. If the scans remain stable, then you could certainly continue on the docetaxel. If not, you will need to speak with your doctor about other possible options. These could include other conventional chemotherapy options or possible clinical trial options.
Q: I have been diagnosed with NSCLC for 8 yrs; negligible growth; I take Tarceva every day. I'm 64 presently and in good health. Is it realistic to think this growth pattern may stay indefinitely?
A: First, congratulations. Stories like yours are what help to give both patients and physicians hope.
Second, in response to your question, the short answer is that we really don't know. "Indefinitely" is a hard word to pin down in any aspect of life. Even as we continue to uncover biological mechanisms for why erlotinib (Tarceva) stops working in some people, it is evident that there is great variability. We still don't have a strong sense for why some patients develop one mechanism of resistance vs. another, and why some patients progress after only a few months while others like you (you certainly aren't the only one) have been able to remain on the drug for many years.
EGFR (epidermal growth factor receptor) Testing
Q: Should all lung cancers be tested for EGFR? Do you recommend any additional "routine" tests for targeted therapies?
A: Great question. To answer that specifically, a collaboration of experts representing the American Society for Investigative Pathology, the Association for Molecular Pathology, and the International Association for the Study of Lung Cancer recently published their recommendations about genetic testing in lung cancer. To quote from their abstract, "The major recommendations are to use testing for EGFR mutations and ALK fusions to guide patient selection for therapy with an epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) inhibitor, respectively, in all patients with advanced-stage adenocarcinoma, regardless of sex, race, smoking history, or other clinical risk factors, and to prioritize EGFR and ALK testing over other molecular predictive tests."
I would wholeheartedly agree that all patients with advanced adenocarcinoma should be tested for EGFR mutations and for ALK rearrangements. There are approved drugs for these (erlotinib and crizotinib, respectively), so the finding of one of these genetic changes has immediate and important implications for a patient's treatment. In patients with other kinds of lung cancer (like small cell or squamous cell), the finding of these genetic changes is extraordinarily rare, so we do not test for EGFR mutations and ALK rearrangements in those types of cancer.
At my center in Boston — Dana-Farber Cancer Institute — we have been exploring the prevalence and potential impact of these and other mutations in patients with advanced-stage adenocarcinoma over the last decade. Together with about a dozen other major centers, we have allied to form the Lung Cancer Mutation Consortium. We have been testing tumors from advanced-stage adenocarcinomas of the lung for mutations in EGFR, KRAS, NRAS, HER2, BRAF, and PI3K. We have been looking for rearrangements in ALK and amplifications in MET. In addition, at our center, we have been looking for rearrangements in ROS and RET. The purpose of this collaboration is several-fold: by combining the expertise, resources, and patient populations of several leading lung cancer groups, we hope to get a better sense of the frequency of each of these tumor genomic changes. Furthermore, by identifying genomically defined patient groups, we can then run clinical trials together more effectively and quickly to try to develop targeted therapies against these targets.
For things like squamous cell lung cancer, the list of potential driver mutations appears to be completely different. Efforts to characterize the squamous cell lung cancer genome have been led by Drs. Peter Hammerman and Matthew Meyerson here at Dana-Farber in Boston, and by Dr. Paul Paik at Memorial Sloan-Kettering in New York. Their research so far has identified other genomic changes of interest in squamous cell carcinomas, implicating genes like FGFR, DDR2, PTEN, and PI3K. How frequent these mutations are — and whether or not we can effectively target them with drugs — remains to be seen, and several clinical trials are underway.
Treatment and Infection
Q: My father, active 82 years young, was diagnosed in October 2012 with inoperable Stage IIIa adenocarcinoma NSCLC. He had 6 weeks of targeted radiation to lymph node (now Stage IIIb) and tumor. Radiation shrank the tumor and lymph node. Malignant pleural effusion, so now Stage IV, and radiation pneumonitis, right lower lobe collapsed. The oncologist wants to start Alimta/ carbo immediately. PET and brain scan show no other masses. He is going to have a drain put in. My question is: shouldn't the infection be cleared before using Alimta? I'm so afraid he'll end up sicker than he is now. The doctors thought the radiation would be enough; however, now with MPE we have some major decisions to make.
A: Thank you for your post. It certainly sounds like a challenging time for your father and your whole family. You are correct in wanting to try to preserve your father's quality of life. We never want the effects of treatment to be worse than the disease itself.
Regarding your question about infection, it is obviously difficult to give specific advice on a case from afar. That having been said, there was nothing in your post that specifically suggests infection. Radiation pneumonitis is not an infection but rather inflammation and scarring caused by the prior radiation therapy; if severe, we think about using steroids to try to treat it. The pleural effusion and right lower lobe collapse may be related to the cancer. There may be other information you didn't include, but otherwise I don't see anything clearly about an infectious issue.
Immunotherapy and Clinical Trials for Advanced Disease
Q: What immunotherapy can be used currently on advanced stage non small cell cancer? There is not much left to offer my friend except late stage trials. Can you suggest where he can go to get one of the substances they are having great success with in melanoma and kidney cancer, e.g., PD-1?
A: The potential role of immunotherapy in lung cancer is indeed generating a lot of early excitement. Specifically, there are a number of agents that are being developed to attempt to spur the immune system into attacking one's cancer. Antibodies that inhibit programmed death 1 (PD-1) found on the surface of activated T-cells try to allow the immune system to recognize cancer cells as foreign and then attack them; antibodies that inhibit programmed death 1 ligand-1 (PD-L1) on tumor cells are trying to do the same thing.
Currently, clinical trials exploring the use of these agents are being conducted at several centers across the country, including my own center, the Dana-Farber Cancer Institute in Boston. All cancer clinical trials must be registered with the National Cancer Institute, which keeps an active, searchable database of available studies. This database can be explored through CancerConnect.com or through the NCI's website at www.cancer.gov. One can search the type and stage of cancer, as well as one's zip code and distance willing to travel; the search engine will then reveal a list of potential trials available within the defined radius. Not every patient will be eligible for every trial. Each trial has specific criteria, including the specific cancer type and the extent of prior therapy. Nonetheless, the search engine will allow your family to explore possible trial options in your area.
In terms of specific agents, there are several immunotherapy drugs that are currently in clinical trials. Some of the PD-1 antibodies include BMS-936558, CT-011, and MK-3475. Some of the PD-L1 antibodies include MDX-1105 (also known as BMS-936559), MedI-4736, and MPDL-3280A. While the specific criteria for potential inclusion and exclusion on each trial will vary, it is important to state that nearly all of these trials exclude patients with any history of autoimmune disease. Because these agents act by revving up the immune system, the risks of doing so in a patient with a history of autoimmune disease could be life-threatening.
Q: I was diagnosed with nsclc in Sept 2011. I was treated with a series of 7 chemo treatments, which included Avastin, Taxol, and carboplatin. In April 2012 I was started on Avastin every 3 weeks and am continuing on that regimen to the present day. My last scans indicated no further growth of lung and spine tumor. The report said no active disease. How long can I stay on Avastin therapy, and what symptoms should I expect if it ceases to do what is designed to do? At present, I am not experiencing any side effects except fatigue. I am continuing to experience numbness in my feet and slight numbness in my finger tips. I am scheduled to have follow-up scans in August.
A: I am glad to hear that your disease remains stable on your current therapy. The use of this combination was pioneered in the ECOG4599 trial led by Alan Sandler, MD. In general, patients receive up to 4-6 cycles of combination therapy with carboplatin, paclitaxel (Taxol), and bevacizumab (Avastin). If disease remains well-controlled at that point, they continue on maintenance bevacizumab every 3 weeks, as you are doing. This can be continued until either it stops working (i.e., disease is growing or spreading) or intolerable or dangerous side effects arise.
It sounds like you are tolerating treatment fairly well. The numbness you are feeling is likely from the prior combination therapy, largely from the paclitaxel (Taxol). It can get better over time, though even when it does improve, it usually does so very slowly. Sometimes agents like gabapentin can help. As for monitoring on bevacizumab therapy, your doctors should continue to follow your blood pressure and check labs, including periodic checks of your urine to look for evidence of protein in the urine. Furthermore, as with any chemotherapy, your doctors should continue to obtain restaging scans to look for evidence of tumor progression, usually done after every 2-3 cycles of treatment.
Suspicious Lung Nodule
Q: I had a 2.5 cm tumor removed 8 years ago (adenocarcinoma). Now there is a 4 mm module in my other lung that my doctor is just watching. Why don't they just take it out now rather than waiting for it to grow? How often does a 4 mm nodule really turn out to be non-cancerous in a person who already had lung cancer?
A: Given a prior history of lung cancer, I understand your apprehension about any nodules seen on your current scans. The reason that we don't surgically remove or irradiate every new lesion that arises is that these may turn out to be noncancerous, and we would hate to subject you to the risks of what might be unnecessary procedures. Furthermore, every surgical resection would incrementally decrease your overall lung function, which could pose problems if done repeatedly and unnecessarily.
Therefore, we try to determine if something is truly cancerous (or at least very, very likely to be cancerous) before subjecting you to surgery. A 4 mm lesion is too small to biopsy and is usually too small to light up on PET/CT. On that basis, it is reasonable to watch these lesions with interval CT scans. Should it grow or change, that is when we might pursue additional studies to help decide upon the need for resection.
To give you a sense of the rate of false-positive results: in the National Lung Screening Trial, 24.2% of patients who underwent screening with low-dose chest CT were found to have a nodule or some other "positive" finding. Of those nodules and findings, over 96% of them were ultimately found to be false-positives (not cancer)!
Q: My mother has Stage IV NSCLC, diagnosed February 2012. She is receiving Navelbine chemo and it has been effective for her thus far — shrinking the tumor by 50% after the first round; her oncologist is having her do a second round. Is this a typical result? If the Navelbine stops being effective, are there any other drugs available?
A: It is great news to hear that your mother is having such a good response to Navelbine (also generically known as vinorelbine). "Typical" is a bit of a weird word — it somewhat implies an expectation. Unfortunately, given the fact that the chemo doesn't work in a fair number of patients and that we can't predict beforehand who will respond and who won't, it's really difficult to define a "typical" outcome. Nonetheless, a 50% shrinkage is certainly a welcomed outcome.
In general, as long as vinorelbine therapy is being tolerated well, we think about continuing it until there is evidence of tumor growth or spread. In terms of how long she might remain on vinorelbine before developing disease progression, this is also rather unpredictable. For many patients, this time to progression is measured in months. However, I have a patient whom I am treating at Dana-Farber (she came in yesterday, in fact) who has been stable on vinorelbine for about a year and a half now, and counting.
There are a number of drugs that are considered for use in non-small cell lung cancer. Some of these include platinum agents (cisplatin, carboplatin), taxanes (paclitaxel or docetaxel), pemetrexed, gemcitabine, targeted agents like erlotinib and crizotinib, and antibodies like bevacizumab. The choice to use any of these agents depends on many factors, including the patient's overall health and other medical conditions, the type of lung cancer subtype, the type and extent of side effects from prior chemotherapy, and — in the case of some of the targeted agents — the presence or absence of specific underlying changes in the cancer's DNA. Beyond the commercially available choices listed above, there might also be clinical trials that could be considered in appropriate patients.
Follow-up after Stage 1 NSCLC
Q: The surgeon removed the stage 1A NSCLC (adenocarcinoma) via RUL lobectomy May of 2009. With no reoccurrence, he now states he would not be worried about a lung reoccurrence; however, he would worry about a primary site in another organ. Should I be asking for a PET at the 5 year post diagnosis? My father had 3 cell types of CA when he passed away. Dad had 11 siblings and 5 of them, that I know of, and a first cousin, also died of CA.
A: I think there are several things to address based on your question:
First, we should talk about the follow-up for lung cancers that have been resected. The standard recommendation has long been to get chest CT scans every 6 months for the first two years after surgery, and then every year thereafter until you reach 5 years post-surgery. While nothing in this field is absolute, the overwhelming majority of lung cancers that are going to recur after surgery do so within 5 years. If a lung cancer has not shown evidence of recurrence within the first 5 years after surgery, it is unlikely that it will come back.
Beyond 5 years, scans are not really looking for recurrence of your old tumor (surveillance) but rather looking for evidence of a new tumor (screening). There is less data to drive decisions about whether and how often to pursue additional chest CT scans in patients with a prior history of resected lung cancer. Several organizations, including the American Association for Thoracic Surgery, are currently endorsing ongoing annual low-dose chest CT scans as a screening tool for patients with a history of resected lung cancer who are more than 5 years out from their surgery. Regarding a PET/CT, there is no data to suggest that these are better or more effective as a screening tool, and so these are not currently recommended as a screening mechanism. If CT detects something of concern, PET/CT might subsequently be used in some cases to see if that lesion lights up.
Another issue you raise regards the potential for a genetic predisposition to cancer in your family. This is a complex issue, one that takes into account not only the percentage of direct family members who have cancer but also things like the types of cancer and ages at diagnosis. Given what sounds like a very strong family history, the best advice I could offer in this regard would be to consider an appointment with a cancer geneticist, who could take a more detailed cancer family history and discuss some of the aspects of further testing. For example, at the Dana-Farber Cancer Institute in Boston, where I work, Dr. Judy Garber runs our Center for Cancer Genetics and Prevention, which specializes in these kinds of cases.
Follow-up Q: Dr. Jackman, thanks for your response. My question regarding the PET scan was to ask you if I should request a total body PET to look for new neoplasms in other areas/organs. I will ask my oncologist if there may be a cancer geneticist in the research center.
Follow-up A: PET/CT as a general screening tool for neoplasms does not have any data to support it and has not been recommended.
Learn more about Dr. Jackman, the Thoracic Oncology Program at Dana-Farber, or CancerConnect's Guest Moderator Ask the Expert Series.
Note: This Ask the Expert Q & A is not intended to be a substitute for healthcare professional medical advice, diagnosis, or treatment. Speak to your healthcare provider about any questions you may have regarding your health.